ABSTRACT/PROJECT SUMMARY Significant Public Health efforts have been made towards salt reduction but most have met with failure. Dietary factors such high sodium/low potassium diets contribute to the development of cardiovascular diseases (CVDs) such as atherosclerosis and high blood pressure (BP). This is important as CVD is the number one killer in the U.S. While the role of these two nutrients on BP is widely accepted, their impact on the vasculature has received less attention. Endothelial dysfunction, characterized by impaired dilation, is an important non- traditional risk factor for atherosclerosis. We have shown that high sodium diets cause endothelial dysfunction, independent of changes in BP (accomplished by testing adults with salt resistant BP). Evidence supporting potassium's beneficial role on vascular health remains unclear although it may be more effective in the presence of a high sodium diet. A purported mechanism responsible for sodium-induced vascular dysfunction is overproduction of reactive oxygen species (ROS) resulting in reduced nitric oxide (NO) production/bioavailability. It has been suggested that potassium can counteract sodium's effects by reducing ROS. Additionally, high sodium diets have been shown to stiffen the endothelium by increasing abundance of the endothelial sodium channel (EnNaC) while potassium's role on EnNaC is unknown. Our central hypothesis is that dietary potassium will protect the vasculature from sodium's harmful effect by preserving NO and reducing oxidative stress and endothelial cell stiffness. We will use three 10-day diets to test our hypothesis (controlled feeding study, crossover design, diet order sequence randomized with washout between diets). We will compare a moderate potassium/high sodium diet (MK/HS; 65 mmol/300 mmol) to a high potassium/high sodium (HK/HS;120 mmol/300 mmol) to assess potassium's protective effect on the vasculature during a fixed sodium intake. We will also compare a moderate potassium/low sodium (MK/LS; 65 mmol/50 mmol) diet to the MK/HS diet to individually confirm salt resistant BP status. Focusing on salt resistant adults allows us to isolate the vascular effects, without the confound of changes in BP (i.e., independent of BP). Rigor will be enhanced by utilizing twenty-four hour ambulatory BP and urine collections during each diet condition; men, women, and minorities will be tested. Brachial artery flow-mediated dilation will be used to assess conduit endothelial- dependent dilation. Cutaneous vasodilation in response to local heating using laser Doppler flowmetry coupled with intradermal microdialysis will be used to assess microvascular function. Venous endothelial cells will be collected for direct assessment of cell stiffness by atomic force microscopy and markers of oxidative stress. We expect to demonstrate that dietary potassium protects the endothelium from the deleterious effects of high sodium by reducing oxidative stress and endothelial cell stiffness and preserving NO. These studies are novel in that they will be the first to comprehensively evaluate the role of dietary potassium on vascular function independent of BP.